Although diagnosing cancer at an early stage can significantly improve survival rate, novel nanoscale technologies that can selectively target and destroy tumor cells while leaving normal cells unharmed, will reduce patient suffering and recovery time. The goal of this project is to develop self-assembled peptide-polymer nanoparticles that can target a high differential dose of a chemotherapeutic agent at constant release rate during the treatment schedule to the tumor support system, thus eliminating harmful side effects and increasing the efficacy of chemotherapy. It is hypothesized that biodegradable self-assembled peptide-polymer nanoparticles, based on cystine-valine(6)-lysine(2)-poly(lactide-co-glycolide fumarate) macromer, due to their narrow size distribution and constant degradation characteristics, can target a high differential dose of the drug to the tumor microenvironment during the course of chemotherapy. To test this hypothesis, the following four tasks are proposed. In the first task, combination of stochastic molecular dynamic and Monte Carlo methods will be used to simulate the effect of chemical composition of the peptide-polymer macromer on particle structure, size, and degradation characteristics. The simulation results will be used to select a subspace in the composition space of the peptide-polymer macromer with 50-150 nm aggregate size and 2-6 weeks degradation time. In the second task, the effect of chemical composition of the peptide-polymer macromer on release kinetics of the cancer drug will be investigated experimentally. In the third task, peptidomimetic nanoparticles will be grafted with the cyclic arginine-glycine-aspartic acid peptide that binds with high specificity to integrin receptors on tumor cells and its effect on tumor cell binding will be determined. In the fourth task, the efficacy of the cancer drug, encapsulated in cyclic peptide grafted nanoparticles, will be determined in a mouse model of breast cancer. Success will be judge by the increase in survival rate and reduction in undesired side effects. The finding of this work has the potential to transform nanoparticle technology from natural or synthetic polymers to hybrid NPs possessing engineering properties as well as biological selectivity. Furthermore, fundamental knowledge will be gained on energetic interaction between the synthetic macromer and amino acids of the peptide which will ultimately result in the discovery of biomimetic nanoparticles with novel engineering as well as biological properties. The intellectual merit is the proof-of-concept that peptidomimetic nanoparticles with unusually narrow size distribution can selectively target high differential doses of a chemotherapeutic agent to tumor microenvironment, while leaving normal tissues unharmed. The broader impact of this work lies in the application of these ideas to areas other than tumor targeting, like protein and gene delivery, biological labeling, detection of pathogens, separation of biological molecules and cells, and as contrast agent in imaging. The ability to fabricate biomimetic self-assembled nanoparticles that can selectively target specific biomolecules, organelles, cells, or tissues not only has the potential for significant breakthroughs in eliminating side effects of chemotherapy but it also advances our knowledge of the relation between biomaterial property and biological response. As part of the outreach program, a doctoral student involved in this project will work with a school teacher to design experiments related to biological applications of nanotechnology for middle school students and to discuss its potential impact on education.
